Introduction and Aim To describe an infant with low GGT cholestasis with certain unique features and throw some light on the expanding genetic spectrum of progressive familial intrahepatic cholestasis (PFIC).

Methods and Results A 4-month-old infant presented with complaints of jaundice since day 7 of life. The stools were pigmented and there was history of repeated episodes of spontaneous bruising and prolonged bleeding from injection sites following vaccination. He was born to a third-degree consanguineously married couple with no previous history of sibling deaths or liver related illness in the family. The antenatal period was uneventful, the boy had a smooth perinatal transition and weighed 2.8kg at birth. He was also failing to thrive and weighed 3.6kg at 4 months. On examination, he was pale, icteric with ecchymotic spots all over the body.

There was firm hepatomegaly along with a palpable spleen. Rest of the systemic examination was unremarkable.

Initial evaluation showed anaemia (hemoglobin- 73g/l), conjugated hyperbilirubinemia (total serum bilirubin- 307.8 μmol/L; direct bilirubin- 195 μmol/L) and deranged liver function tests (aspartate transaminase- 290 IU/L; alanine transaminase- 192 IU/L; alkaline phosphatase- 923 IU/L; total serum protein- 56 g/l; albumin- 35 g/l). The coagulation parameters were also deranged with a prothrombin time of 18 sec (normal 10–12 sec) and an international normalized ratio of 1.7 (normal 0.9–1.1) which persisted even after parenteral vitamin K administration. The gamma glutamyl transferase levels were low (GGT- 22 IU/L). Ultrasonography of the abdomen revealed hepatosplenomegaly with visualized gall bladder and common bile duct. Further work up showed markedly elevated alfafeto protein (AFP) levels (AFP- 130000 U/ml; normal <10 U/ml) on multiple occasions. Urine for succinyl acetone was negative and erythrocyte galactose-1-phosphate uridyl transferase (GALT) enzyme was within normal limits. With the low-normal GGT cholestasis, a possibility of progressive familial intrahepatic cholestasis (PFIC) was considered and genetic analysis was sought. Next generation sequencing a homozygous deletion on chromosome 12 [(c.(109+1_110–1_475+1_476–1) del] involving the exon 1 region of NR1H4 gene.

Summary and Conclusion The NR1H4 gene encodes for farnesoid x receptor (FXR), which is the nuclear receptor transcription factor regulating bile acid synthesis and BSEP expression. Micro-deletion involving first two exons of this gene has previously been reported in the literature in patients presenting with PFIC phenotype. PFIC resulting from mutations in the genes encoding FXR is termed PFIC-5, which is very rare and only eight cases have been reported in literature till date. It shares some similarities with the PFIC type 2 and is characterised by early onset cholestasis, markedly elevated AFP, hyperammonemia and vitamin K independent coagulopathy; all the features which were seen in the index case. Progression to cirrhosis and end stage liver disease can be rapid.